Process for preparation of hiv protease inhibitors

ABSTRACT

A process for the synthesis of bisfuran intermediates of formula (0) useful for preparing antiviral HIV protease inhibitor compounds is hereby disclosed. Furthermore disclosed is a HIV protease inhibitor of formula (IV) as well as various intermediates thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/787,126, filed Mar. 29, 2006.

FIELD OF THE. INVENTION

The invention relates generally to processes for the preparation ofantiviral compounds with anti-HIV protease properties. The inventionrelates to the methods for the preparation of carbamate sulfonamideamino phosphonate esters and intermediates thereof. The invention alsorelates to the novel intermediates prepared by these methods. Thecarbamate sulfonamide amino phosphonate esters prepared by the presentmethods are HIV protease inhibitors, useful for the treatment of humanauto immunodeficiency syndrome (AIDS).

BACKGROUND OF THE INVENTION

AIDS is a major public health problem worldwide. Although drugstargeting HIV viruses are in wide use and have shown effectiveness,toxicity and development of resistant strains have limited theirusefulness. Assay methods capable of determining the presence, absenceor amounts of HIV viruses are of practical utility in the search forinhibitors as well as for diagnosing the presence of HIV.

A conventional process for preparation of a HIV protease inhibitor (PI)of Formula I

is lengthy, affords a low yield of approximately 1%, is variablyreproducible, requiring numerous chromatographic purification steps, andemploys undesirable reagents, such as ozone, sodium cyanoborohydride,and tributyltin hydride. The compound of Formula I is an HIV proteaseinhibitor which has been made and disclosed in WO2003/090690.

Methods for the preparation of the bisfuran alcohol intermediate used inthe synthesis of the compound of formula I have been described byPezechk (Pezechk, M. et al., Tetrahedron Letters, 1986, 27, 3715.) andGhosh (Ghosh, A. K. et al., J. Med. Chem., 1994, 37, 2506; Ghosh A. K.et al., J. Med. Chem., 1996, 39, 3278; Ghosh, A. K. et al., TetrahedronLetters, 1995, 36, 505).

Scheme 1 shows the bisfuran alcohol synthesis from Ghosh, A. K. et al.,Tetrahedron Letters, 1995, 36, 505).

Conventional methods require multiple steps and the use of toxicreagents. In one of the methods (Ghosh, A. K. et al., TetrahedronLetters, 1995, 36, 505), resolution of a racemic mixture was achieved byexposure to an immobilized enzyme followed by chromatographicseparation.

Reactive carbonate esters have been prepared from bisfuran alcohol (1)and dipyridyl carbonate (Ghosh A. K. et al., J. Med. Chem., 1996, 39,3278), and p-nitrophenol chloroformate (X. Chen et al., Bioorganic andMedicinal Chemistry Letters, 1996, 6, 2847). These reagents couple withnucleophilic reaction partners, but do not always display theappropriate reactivity and efficiency.

Methods exist for the preparation of chiral haloalcohols derived fromN-protected amino acids (Albeck, A. et al., Tetrahedron, 1994, 50,6333). Methods for the conversion of such chloroalcohols to carbamatesulfonamide derivatives are known (Malik, A. et al., WO 01/46120A1). Thehalohydrins can also be converted to epoxides and converted to carbamatesulfonamide derivatives in a similar manner (WO 03/090690).

Preparation of Carbamate Derivatives of Aminophosphonic Acids andsubsequent conversion to phosphonate mono- and diesters have beendescribed in Yamauchi, K. et al., J. Org. Chem., 1984, 49, 1158;Yamauchi, K. et al., J. Chem. Soc. Perkin Trans. I, 1986, 765.

Aminoethyl phosphonate diesters can be prepared by a process involvingacylation of an amino phosphonic acid with acyl halides or benzylchloroformate (CBZCI) to form compounds of Formula VII

Compounds of Formula VII can be activated and condensed with phenol toform a compound of Formula VIII

A compound of Formula VIII can be activated and condensed with a secondalcohol or phenol to form IX

A compound of Formula IX can be deacylated to form an amino phosphonatecompound of Formula X

A compound of Formula X can be isolated as a salt of an organic orinorganic acid.

The Ghosh process for bisfuran alcohol (Ghosh, A. K. et al, J. Org.Chem., 1995, 36, 505) requires the use of tributyltin hydride and ozone.

The free base of a compound of Formula I is non-crystalline andhygroscopic with limited stability in protic solvents.

Thus, there exists a need to develop syntheses of more stable forms ofthe PI of Formula I. There also exists a need to develop more efficientprocesses of synthesizing the PI of Formula I.

SUMMARY OF THE INVENTION

The present invention provides improved methods to bisfuran alcoholderivatives, amino phosphonate derivatives and a process to preparecarbamate sulfonamide aminoethyl phosphonate diesters useful for thetreatment of human auto immunodeficiency syndrome (AIDS).

In one embodiment, the invention provides a process for the preparationof a bisfuran alcohol of Formula 0:

comprising

reacting 2,3-dihydrofuran and glycoaldehyde or glycoaldehyde dimer inthe presence of a lanthanide or transition metal catalyst to form thebisfuran alcohol of Formula 0.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When tradenames are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

“Lanthanides” refers to the following elements and their ions: La, Ce,Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu.

“Transition metals” refer to the following elements and their ions: Sc,Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag,Cd, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg.

Ligands comprising the metal catalysts may be chiral, achiral orracemic.

Schemes and Examples

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Exemplary Embodiments

In one embodiment, the invention provides a compound of Formula C and apharmaceutically acceptable salt thereof:

In another embodiment, the invention provides a process of preparing acompound of Formula M comprising

a) treating a compound of Formula E with an amine such as1-amino-2-methylpropane

to form a compound of Formula F

b) treating the compound of Formula F with a compound of Formula G

to form a compound of Formula C

c) treating the compound of Formula C with a reducing agent to form thecompound of Formula M

Typical reducing agent which can be used to effect the transformation ofthe nitrile moiety to the carboxaldehyde moiety can found in Larock,Richard, C. “Comprehensive Organic Transformations 2^(nd) Ed. 1999 JohnWiley and Sons publisher, pages 1271-1272.

In another embodiment, the invention provides a compound of Formula M:

In another embodiment, the invention provides a process for thepreparation of a compound of Formula M:

comprising

treating a compound of Formula C with a reducing agent to form thecompound of Formula M

In another embodiment, the invention provides a process of preparing thecompound of Formula M, wherein the reducing agent is diisobutyl aluminumhydride.

In another embodiment, the invention provides a process of preparing acompound of Formula 0, further comprising

treating the bisfuran alcohol of Formula 0 with disuccinimidyldicarbonate to form a compound of Formula L1

In another embodiment, the invention provides a process of preparing thecompound of Formula 0, further comprising

treating the bisfuran alcohol of Formula 0 withbis(p-nitrophenyl)carbonate or p-nitrophenol chloroformate to form acompound of Formula L2

In another embodiment, the invention provides a process of preparing thecompound of Formula 0, further comprising

treating the bisfuran alcohol of Formula 0 with dipyridyl carbonate toform a compound of Formula L3

In another embodiment, the invention provides a compound andpharmaceutically acceptable salts thereof having Formula N

In another embodiment, the invention provides a compound andpharmaceutically acceptable salts thereof having Formula A

In another embodiment, the invention provides a process for thepreparation of carbamate sulfonamide amino phosphonate esters whichcomprises:

a) addition of a dihydrofuran to a glycoaldehyde or glycoaldehyde dimerin the presence of a Yb, Pr, Cu, Eu or Sc catalyst to form the bisfuranalcohol of Formula 0

b) treating the reaction product of step (a) with disuccinimidyldicarbonate, bis(p-nitro)phenyl carbonate, p-nitrophenol chloroformate,or dipyridyl carbonate to form a compound of Formula L1, Formula L2,Formula L2, or Formula L3, respectively,

c) treating a compound of Formula E with an amine

to form a compound of Formula F

d) treating a compound of Formula F with a compound of Formula G

to form a compound of Formula C

e) treating a compound of Formula C with a reducing agent to form acompound of Formula M

f) deprotecting a compound of Formula M with trifluoroacetic acid,hydrochloric acid, toluenesulfonic acid, methanesulfonic acid,benzenesulfonic acid, hydrobromic acid or another suitable acid aslisted in Protective Groups in Organic Chemistry, Theodora W. Greene,John Wiley & Sons, Inc., New York, 1991, to form a compound of Formula N

g) treating a compound of Formula N with a compound of Formula L, L2, orL3 to form a compound of Formula A

h) treating a compound of Formula A with a compound of Formula J

to form a compound of Formula I

i) treating a compound of Formula I with adipic acid to form a salt offormula IV

In another embodiment, the invention provides a salt having Formula IV:

The salt of formula IV was prepared and has a melting point of 118°C.-121° C. The free base of the salt of formula IV is an HIV proteaseinhibitor which has been made and disclosed in WO2003/090690, which isherein incorporated by reference. The salt of Formula IV is also an HIVprotease inhibitor useful for treating patients infected by HIV.

TABLE 1 Chiral catalysts in bisfuran alcohol formation.

Conversion GC Analysis¹ Entry Conditions Catalyst Solvent (%) [(−)-1 to(+)-1] 1 50° C., 5 hr Yb(hfc)₃ (+) DHF 100 49 to 51 2 50° C., 5 hrYb(hfc)₃ (−) DHF 100 50 to 50 3 50° C., 5 hr Eu(hfc)₃ (+) DHF 100 48 to52 4 r. t., 20 hr Yb(fod)₃, S- MTBE 100 50 to 50 binaphthol 5 50° C., 5hr Yb(tfc)₃ (+) DHF 100 52 to 48 6 50° C., 5 hr Pr(tfc)₃ (+) DHF 100 56to 44 7 50° C., 2.5 hr Yb[(R)-(−)-BNP]₃ DHF 100 60:40 8 30° C., 12 hrYb[(R)-(−)-BNP]₃ DHF 100 59:41 9 50° C., 5 hr Yb[(R)-(−)-BNP]₃ DHF 10065:35 10 r. t., 5 hr Cu[Pybox] DHF Polymerized DNA 11 50° C., 5 hrCu[Pybox] DHF Polymerized DNA 12 r. t., 5 hr Cu[Pybox] DCM <5 DNA 13 50°C., 5 hr Cu[Pybox] DCM 0 DNA 14 r. t., 20 hr Cu[Pybox] DHF/DCM 0 DNA DHF= dihydrofuran, DCM = dichloromethane, MTBE = methyl-t-butylether. ¹GCanalyses were performed by derivatizing bisfuran alcohol to thetrifluoroacetate with trifluoroacetic anhydride in DCM.

TABLE 2 Use of scandium (III) catalyst and chiral ligands to directlyaccess (−)-1.

Catalyt Ligand Temp Time Conversion GC Analysis¹ Entry Mol % Mo l% (°C.) (hrs) Solvent (%) [(−) to (+)] 1 3.4 7.5 r. t. (3)5 DCM 100 79:21 23.4 3.6 −10 to (3)5 DCM 100 62:38 r. t. 3 20.0 21.4 r. t.  (3)24 DCM <10NA 4 3.4 7.6 r. t.  (3)24 DCM <10 NA 5 3.4 7.5 r. t. (3)5 DCM 100 78:226 3.35 9.37 50 (3)5 DCM <10 NA 7 3.35 9.37 r. t. (3)5 THF <10 NA 8 3.359.37 r. t. (3)5 MTBE/ <10 NA DME 9 3.35 9.37 0 (3)5 THF 100 75:25 103.35 9.37 r. t. (3)5 MeCN 100 74:26 11 6.7 18.74 r. t. (3)5 DCM 10082:18 12 10.0 60.0 r. t. (3)5 DCM 100 82:18 13 6.7 18.74 r. t. (3)5 TFT<5 NA 14 6.7 18.74 0 (3)5 DCM 100 85:15 15 6.7 18.74 0 (3)6 CHCl₃ >10 NA16 6.7 18.74 −78 (3)6 DCM 0 NA 17 6.7 18.74 −20 (3)6 DCM <5 NA 18 6.718.74 0 to −5  (5)68 DCM 100 82:18 TFT = trifluorotoluene, DME =dimethavethane, DCM = dichloromethane, MTBE = methyl-t-butylether, THF =tetrahydrofuran. ¹GC analyses were performed by derivatizing bisfuranalcohol to the trifluoroacetate with trifluoroacetic anhydride in DCM

TABLE 3 Use of catalystsand chiral ligands to directly access (−)-1.

GC Analysis¹ Catalyst Catalyst Ligand Ligand Temp Time [(−) to EntryUsed Mol % Used Mol % (° C.) (hrs) Solvent (+)] 1 Sc(OTf)₃ 3.4 2 7.5 r.t.  (3)24 DCM Messy 2 Sc(OTf)₃ 3.4 2 7.5 r. t. (3)5 DCM 26:74 3 Yb(OTf)₃3.4 2 7.6 r. t. (3)3 DCM 50:50 4 Sc(OTf)₃ 3.4 2 12.0 r. t. (3)5 DCM23:77 5 Sc(OTf)₃ 3.35 3 7.54 r. t. (3)5 DCM 51:49 6 Sc(OTf)₃ 3.5 4 7.5r. t. (3)5 DCM 57:43 7 Cu(OTf)₂ 4.8 5 5.6 r. t. (0.5)3   DCM 52:48 8Cu(OTf)₂ 5.6 5 13.97 r. t. (3)5 DCM 52:48 9 Yb(OTf)₃ 6.7 1 18.74 r. t.(3)5 DCM 61:39 ¹GC analyses were performed by derivatizing bisfuranalcohol to the trifluoroacetate with trifluoroacetic anhydride in DCM.

TABLE 4 Use of column method for enantiomeric resolution of (±)-bisfuran

Re- Lipase Amt of Rate sidence Total (ROAc Optical Activity Lipase (mL/Time Time to ROH Purity Yield Entry (U/g) (g) min) (min) (hrs) (10:1) (%ee) (%) 1 1925 18.6 17 1.8 10.5 1.5:1.0 97.2 32 2 1925 22.7 164 0.5219.0 NA 98.2 42 3 1925 275.6 2000 0.8 14.5 1.2:1.0 97.2 33

-   Yamanuchi, K. et al, J. Org. Chem., 1984, 49, 1158; Chapman, H. et    al; Nucl. Nucleotid. Nucleic Acids, 2001, 20, 621

The invention will now be illustrated by the following non-limitingExamples.

Examples

Preparation of, (3R,3aS,6aR) Hexahydrofuro[2,3-b]furan-3-ol, (1)

To a reaction vessel, charge glycolaldehyde dimer (4.45 kg), Yb(fod)₃catalyst (0.29 kg) and dihydrofuran (20.5 kg). Agitate contents to mixand heat to 50° C. for ˜5 hours. Concentrate reaction content to a crudeoil, dissolve in saturated aqueous NaHCO₃ solution (60 kg), and washwith dichloromethane (6 kg). Charge dichloromethane (58 kg), KBr (0.89kg), TEMPO (0.116 kg) to the aqueous layer and cool the mixture to 0° C.Slowly add to this mixture with sodium hypochlorite (NaOCl, ˜11% Cl, 55kg). Upon completion of reaction, allow the organic and aqueous layersto separate. Wash the aqueous layer with dichloromethane (29 kg).Combine the organic layers and wash with water, 10% HCl with KI, and 10%sodium thiosulfate. Dry the organic layer over sodium sulfate, filterthe solids, and cool the filtrate to below 0° C. Add a solution ofsodium borohydride (0.36 kg) in ethanol (7.1 kg) while maintainingreaction content temperature below 0° C. Upon completion of reaction,add acetic acid (1.4 kg) and water (13.4 kg) to quench. Concentratemixture by vacuum distillation. To the resulting crude oil/semi-solidmixture, add ethyl acetate (31 kg). Dry organic layer over sodiumsulfate, filter solids, and concentrate via vacuum distillation toisolate (±)-1 as an oil. Enzymatic Resolution. Charge ethylene glycoldimethyl ether (DME, 14.7 kg) and acetic anhydride (4.6 kg) to the crudeproduct oil. Circulate this solution through a column packed with amixture of Lipase PS-C “Amano I” (0.36 kg) and sand (6 kg). Uponcompletion of the enantiomeric resolution, concentrate the solution viavacuum distillation. Add water (18 kg) to dissolve the product and washthe solution with dichloromethane (28 kg). Concentrate the productcontaining aqueous layer via vacuum distillation. Dissolve the resultingoil in ethyl acetate (16 kg) and dry over sodium sulfate. Additionalproduct can be isolated by back extracting the dichloromethane layerwith water several times. Concentrate the combined water layers viavacuum distillation. Dissolve the resulting oil in ethyl acetate; dryover sodium sulfate, and filter solids. Concentrate the combined ethylacetate layers via vacuum distillation to afford the product, (3R,3αS,6αR) hexahydrofuro[2,3-b]furan-3-ol, (−)-1, as an oil (1.6 kg, 97% ee,33% yield) contaminated with a approximately 15 wt % of thecorresponding acetate. Analytical data: ¹H NMR (DMSO-d6, 300 MHz) δ 5.52(dd, 1H), 4.25-4.15 (m, 1H), 3.85-175 (m, 2H), 3.7-3.6 (m, 1H), 3.3 (t,1H), 2.75-2.65 (m, 1H), 2.23-2.13 (m, 1H), 1.75-1.6 (m, 1H).

Preparation of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl 4-NitrophenylCarbonate)

Charge to a reaction vessel with bis(4-nitrophenyl)carbonate (2.85 kg)and dichloromethane (33.4 kg). Add to this solution with(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, (−)-1 (1.2 kg, 98.5% ee,contaminated with ˜36% acetate) dissolved in dichloromethane (6.7 kg).Charge triethylamine (1.6 kg) and agitate the resulting reactioncontents at 20-25° C. Upon completion of reaction, wash the contentswith water (16.8 kg). Separate the layers and concentrate thedichloromethane layer via vacuum distillation. Dissolve the productcontaining oil in ethyl acetate (21.2 kg) and sequentially wash withwater, aqueous potassium carbonate solution and brine. Dry the ethylacetate layer over sodium sulfate, filter solids, and concentrate viavacuum distillation. Dissolve the concentrated product mixture in ethylacetate (9.3 kg) and heat to 45° C. Charge hexanes (6.7 kg) slowly andcool the final mixture slowly to 0° C. Filter the resulting slurry toisolate 12. Wash the solid cake with a solution of ethyl acetate andhexanes (1:1 v/v, 5.3 kg). Dry the product to constant weight affording1.5 kg of 12 (55%) as an off-white solid. Additional product may beobtained by concentrating the mother liquor via vacuum distillation andrepeating the crystallization procedure. Analytical data: ¹H NMR (CDCl₃,300 MHz) δ 8.3 (d, 2H), 7.4 (d, 2H), 5.8 (d, 1H) 5.3-5.2 (m, 1H),4.2-4.1 (m, 1H), 4.1-3.9 (m, 3H), 3.25-3.1 (m, 1H), 2.3-2.1 (m, 1H),2.1-1.9 (m, 1H); HPLC AN=98.5%.

Procedure for Formula 12,{(2S,3R)-1-(4-Benzyloxy-benzyl)-2-hydroxy-3-[isobutyl-(4-methoxy-benzenesulfonyl)-amino]-propyl}-[3R,3aS,6aR]-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

A flask is charged with Formula 27 (1.3 Kg), followed by Formula 12(0.65 Kg) and ethyl acetate (7.2 Kg) and agitated and triethylamine(0.65 Kg) and dimethylaminopyridine (24 g) added and agitated at ambienttemperature for several hours. The reaction mixture is washedsequentially with water (8 Kg), aqueous saturated NaHCO₃ (8 L) anddilute aqueous HCl (8 L) and brine (8 L). The reaction mixture ischarged with activated charcoal (0.13 Kg), stirred for several hours,filtered through celite and rinsed with ethyl acetate. Heptane (6 L) isadded, the mixture agitated for several hours and the product collectedby filtration, and rinsed with 1:1 EtOAc/Heptane. The product is driedto constant weight affording 1 Kg of Formula 12 (70%) as an off whitesolid, mp 127.5° C., HPLC purity 98.4. ¹H NMR (CDCl₃) 7.7-7.75 (d, 2H),7.26-7.48 (m, 5H), 7.12-7.20 (d, 2H), 6.96-7.03 (d, 2H), 6.85-6.94 (d,2H), 5.65 (d, 1H), 5.3 (broad d, 1H), 5.01 (s, 2H), 4.96-5.06 (broad,1H), 3.63-3.96 (m, 7H), 3.84 (s, 3H), 2.62-3.20 (m, 7H), 1.8-1.95 (m,1H), 1.40-1.69 (m, 2H), 0.95 (dd, 6H).

Procedure for Formula 13, {[1S,2R}-2-Hydroxy-1-(4-hydroxy-benzyl)-3-[N-isobutyl-(N-4-methoxybenzenesulfonyl)-amino]propyl}-carbamicacid hexahydro-[3R,3aS,6aR]-furo[2,3-b]furan-3-yl ester

A flask is charged with Formula 12 (1 Kg) and flushed with nitrogen.Palladium on activated carbon, 10 wt %, wet, (0.2 Kg) is added, theflask flushed with nitrogen and ethyl acetate (10 L) added and themixture is heated to 50° C. and hydrogen is sparged into reactionmixture for 2.5 h until reaction is complete. The mixture is spargedwith nitrogen and then filtered through celite under nitrogen and thenrinsed with ethyl acetate. The filtrate is concentrated to 2.5 L andheptane (7.5 L) added to the warm solution. The resultant slurry iscooled in an ice bath, collected and washed with n-heptane and dried toconstant weight affording Formula 13 as a solid, 0.82 Kg, mp: twoendotherms at 98.2 and 133.8° C., HPLC purity 97.4%. ¹H NMR (CDCl₃)7.61-7.75 (d, 2H), 7.01-7.10 (m, 2H), 6.91-6.99 (d, 2H), 6.63-6.79 (d,2H), 5.62 (d, 2H), 5.51 (broad s, 1H), 4.96-5.09 (d, 2H), 3.81 (s, 3H),3.59-3.98 (m, 6H), 2.62-3.18 (m, 7H), 1.42-1.91 (m, 3H), 0.78-0.95 (dd,6H).

Procedure for Formula 14, Trifluoro-methanesulfonic acid4-(2S,3R)-{2-([2R,3S]-hexahydro-furo[2,3-b]furan-(3R)-3-yloxycarbonylamino)-3-hydroxy-4-[N-isobutyl-(N-4-methoxybenzenesulfonyl)-amino]-butyl}-phenylester

Formula 13 (0.82 Kg) and dichloromethane (8 Kg) were charged into aflask, and gently warmed to dissolve the Formula 13. A separate flaskwas charged with N-phenyltriflimide (0.61 Kg) and dichloromethane (2.6Kg) and gently warmed to obtain a solution. A solution of triflatingagent was transferred into the solution containing Formula 13 and cesiumcarbonate (0.55 Kg) was added and stirring continued at ambienttemperature for several hours until reaction was complete. Water (4 Kg)was added, the layers separated, the aqueous back extracted withdichloromethane and the combined organic layers dried over anhydroussodium sulfate. The solution was filtered and concentrated to a smallvolume and diluted sequentially with methyl tert butyl ether (7 L) andheptane (16 L) and stirred at ambient temperature to obtain a solidwhich was collected and dried to constant weight to provide Formula 14as a solid, 0.68 Kg, mp 133.7° C., ¹⁹F NMR (CDCl₃)-73.5 ppm, HPLC purity97.2%. ¹H NMR (CDCl₃) 7.70-7.78 (d, 2H), 7.29-7.38 (d, 2H), 7.16-7.23(d, 2H), 6.96-7.06 (d, 2H), 5.67 (d, 1H), 4.95-5.04 (m, 2H), 3.87 (s,3H), 3.64-4.01 (m, 7H), 2.78-3.21 (m, 7H), 1.51-1.90 (m, 3H), 0.87-0.97(dd, 6H).

Procedure for Formula 15,{(1S,2R)-[1-(4-Formyl-benzyl)]-(2R)-2-hydroxy-3-[N-isobutyl-(N-4-methoxy-benzenesulfonyl)-amino]-propyl}-carbamicacid [3R,3aS,6aR]-hexahydrofuro[2,3-b]furan-3-yl ester

A flask is charged with Formula 14 (0.15 Kg) followed by Pd(OAc)₂ (0.06Kg), dppp. (0.1 Kg), dimethylformamide (1.9 Kg) and sequentiallyevacuated by vacuum and purged with nitrogen several times and thenheated under nitrogen to an internal temperature of 60 to 65° C. andlithium chloride (3 g) is added. The mixture is heated at 65-70° C. andthe mixture is sparged with carbon monoxide for 30 minutes.Triethylamine (86 g) is charged to the solution, followed by slowaddition of triethylsilane (0.05 Kg). The reaction is maintained at65-70° C. under a CO atmosphere until the reaction is complete. Thereaction mixture is cooled to ambient temperature, diluted with ethylacetate (1.8 Kg) and washed with water (4 Kg). The ethyl acetate is backextracted with water (1 Kg) and the combined water layers back extractedwith ethyl acetate (0.5 Kg). The combined ethyl acetate extracts arewashed with water several times and the ethyl acetate filtered throughcelite, diluted with acetonitrile (0.2 Kg). HF (48% in water, 0.23 Kg)and saturated NaHCO₃ (3 Kg) are added, the reaction mixture is separatedand the aqueous layer discarded. The organic layer is dried overanhydrous sodium sulfate, filtered and the filtrate heated to atemperature of 50-55° C., treated with trimercaptotriazine (23 g) forseveral minutes, activated carbon (10 g) added, the mixture heated at50-55° C. for at least 30 minutes, cooled to ambient temperature andfiltered through a pad of celite. The filtrate is washed with saturatedNaHCO₃ (0.7 Kg), separated, dried over anhydrous sodium sulfate,filtered, and concentrated and the residue purified by silica gel columnchromatography eluting with a mixture of ethyl acetate and heptane. Thefractions containing desired Formula 15 are collected and concentratedto afford a white solid which is recrystallized by dissolving inethylene glycol dimethyl ether at elevated temperature and slow additionof heptane followed by cooling to ambient temperature. Collection of thesolid by filtration, rinsing with heptane and drying to constant weightprovides Formula 15 as a white solid, 72%, 0.125 Kg, mp 140.2° C., HPLCpurity 98.3%. ¹H NMR (CDCl₃) 9.98 (s, 1H), 7.80-7.85 (d, 2H), 7.67-7.76(d, 2H), 7.39-7.45 (d, 2H), 6.95-7.04 (d, 2H), 5.65 (d, 1H), 4.96-5.12(m, 2H), 3.85 (s, 3H), 3.64-4.02 (m, 7H), 2.75-3.21 (m, 7H), 1.72-1.89(m, 1H), 1.42-1.70 (m, 2H), 0.84-0.98, dd, 6H).

Procedure for Formula 16, 2-(N-benzyloxycarbamoyl)-aminoethylphosphonicacid

A flask is charged with deionized water (9 Kg), inerted, agitated andcharged with sodium hydroxide (2.7 Kg) in portions to maintain thetemperature below 35° C.

Aminoethyl phosphonic acid (AEP, 3 Kg) is charged into the flask inportions. Benzyl chloroformate (5.6 Kg) is added in several portionscontrolling the temperature at approximately between 40° C. The mixtureis allowed to react at ambient temperature for several hours untilreaction is complete. The mixture is extracted twice with ethyl acetate(16 Kg portions). The aqueous layer is acidified with concentrated HClto pH 1.3 and aged for several hours. The solid is collected and washedwith acetonitrile (2.3 Kg). The solid and methanol (9.6 Kg) is thencharged to a flask and treated with Dowex resin (8.7 Kg) that has beenprewashed with water and methanol. The mixture is stirred at ambienttemperature for 1 h, filtered and rinsed with methanol (3 Kg). Thefiltrate is concentrated to thick oil, diluted with acetonitrile andazeotroped repeatedly with acetonitrile until residual methanol isremoved. The solution is then diluted with acetonitrile, heated toattain a solution, filtered and allowed to cool gradually to ice bathtemperature.

The solid is collected and dried to constant weight affording Formula 16(CBZ-AEP) 4.8 Kg, 77%, mp 107° C., ³¹P NMR (D₂O) 26.6 ppm. ¹H NMR (D₂O)7.2-7.36 (broad s, 5H), 4.95 (broad s, 2H), 3.16-3.30 (m, 2H), 1.78-1.94(m, 2H).

Procedure for Formula 17,Phenyl-2-(N-benzyloxycarbamoyl)-aminoethylphosphonate

CBZ-AEP (2.5 Kg) and acetonitrile (3.1 Kg) were stirred and heated to60-65° C. In a separate flask, phenol (4.5 Kg) and acetonitrile (3.5 Kg)were warmed to afford a solution and this solution was charged to theCBZ-AEP mixture and stirred until a solution was obtained. To thissolution was charged a slurry of 4-dimethylaminopyridine (DMAP, 1.4 Kg)in acetonitrile (3.1 Kg). In a separate flask was charged acetonitrile(0.8 Kg) and dicyclohexylcarbodiimide (3 Kg) was charged. This DCCsolution was added to the warm AEP solution. As soon as the addition wascomplete, the reaction mixture was refluxed for several hours until thereaction was complete. The reaction mixture was cooled to ambienttemperature, filtered and the filtrate concentrated and diluted withwater (20 L) and aqueous NaOH. The solution was extracted twice withethyl acetate (13.5 L). The aqueous phase was acidified to pH of 1.0 byaddition of 6M HCl, the resultant solid collected and reslurried withwater (19 L) and collected again, and dried to constant weight toprovide Formula 17 as a white solid, 2.47 Kg, mp 124° C., HPLC purity99.2%, ³¹P NMR (CDCl₃) 29.8 ppm (˜90%) and 28.6 ppm (˜10%) due torotamers of the carbamate functional group. ¹H NMR (CDCl₃) 7.05-7.40 (m,10H), 5.10 (broad s, 2H), 3.41-3.59 (m, 2H), 2.01-2.20 (m, 2H).

Procedure for formula 18, Phenyl,(ethyl(S)-2-propionyl)-2-(N-benzyloxycarbamoyl)-aminoethylphosphonate

Formula 17 (4.8 kg) was charged to the reactor along with toluene (24kg) and DMF (4 g). The mixture was warmed to 70° C. SOCl₂ was added overtime while maintaining 67-72° C. internal contents temperature, and thereaction agitated at 75° C. until the reaction was complete. Thesolution was cooled to 45° C. and concentrated under vacuum to approx.half volume. In a separate reactor a dry solution of (S)-ethyl lactate(1.9 kg), toluene (15 kg), and pyridine (1.5 kg) was prepared and cooledto −1° C. The chloridate solution was added slowly while maintaining aninternal temperature of −3 to 3° C. and then the resulting solution waswarmed to 20° C. and agitated until the reaction was complete. Thereaction was added to a solution of 10% aq. citric acid (10 kg), thelayers separated and the organic layer washed with 10% aq. NaH₂PO₄ (10kg). The organic layer was dried over anhydrous sodium sulfate (5 kg),concentrated and evaporated from ethyl acetate (4 kg) to a viscous oilwhich is purified by passing through silica gel plug (9:2 kg) elutingwith a mixture of ethyl acetate and heptane. The fractions containingFormula 17 were combined and concentrated to afford an oil. The solventwas exchanged by evaporating twice with acetonitrile (2×3 kg) to affordan thick liquid (4.7 kg, 80%) with HPLC purity 98% as a mixture of twodiastereomers (corrected for benzyl chloride).

The mixture of isomers was separated on Chromasil silica gel, elutingwith a mixture of ethyl acetate and heptane. The desired isomer Formula20, displayed the following physical data: Oil, ³¹P NMR (CDCl₃) 26.1(˜90%) and 25.4 (˜10%) due to rotamers of the carbamate functionalgroup; ¹H NMR (CDCl₃) 7.24-7.4 (m, 8H), 7.14-7.21 (m, 2H), 5.65 (broads, 1H), 5.1 (s, 2H), 5.02-5.06 (m, 1H), 4.12-4.17 (q, 2H), 3.52-3.70 (m,2H), 2.15-2.36 (m, 2H), 1.57 (d, 3H), 1.22 (t, 3H).

Procedure for Formula 19, Phenyl, (ethyl(S)-2-propionyl)-2-aminoethylphosphonate, acetate salt

A flask is charged with palladium on activated carbon, 10 wt %, wet(0.28 Kg), acetic acid (0.15 L) and Formula 20 (0.56 Kg) and ethanol(5.6 L) and the flask is sparged with nitrogen for approximately 30minutes. Hydrogen is sparged into reaction mixture for several hoursuntil the starting material is consumed. The reaction mixture is spargedwith nitrogen for 60 minutes and the reaction mixture is filteredthrough celite and washed with ethyl alcohol (2 L). The filtrate isconcentrated at ambient temperature to a small volume, diluted withacetonitrile (5.6 L), concentrated to half volume, and treated withactivated carbon (0.3 Kg), filtered through celite and washed withacetonitrile (2.5 L). The filtrate is evaporated at ambient temperatureand diluted with acetonitrile and evaporated. This is repeated severaltimes to remove all ethanol and water and the solution finallyconcentrated to a small volume and stored at 5° C. Evaporation of analiquot provided yield. Oil, 90%, 0.49 Kg, ³¹P NMR (CDCl₃) 25.2. Thematerial was used in the next step without further purification.

Procedure for Formula 21,2-[(2S,3R)-4-[((4-methoxybenzene)sulfonyl)(2-methylpropyl)amino]-3-(hydroxy)butyl]-[[[[(phenoxy)(2-(2R)-propionicacid ethyl ester)oxy]phosphinyl]ethylamino]benzyl]-[carbamicacid-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester]hexanedioate salt(1:1)

A flask is charged with Formula 15 (0.5 Kg), acetonitrile (1.6 L) and asolution of Formula 19 (0.46 Kg) in acetonitrile (1 L) followed byacetonitrile (2.4 L). The mixture is stirred at ambient temperatureseveral hours. NaBH(OAc)₃ (0.27 Kg) is added in portions over time atambient temperature to maintain at ambient temperature. The reactionmixture is stirred several hours until reaction is complete. Celite(0.24 Kg) is added and the reaction mixture is filtered and washed withacetonitrile and isopropyl acetate. The filtrate is concentrated to asmall volume and diluted with isopropyl acetate (12.5 L) and washedsequentially with saturated NaHCO₃ three-four times (7.5 L portions),brine (3.8 L), the organic solution dried over sodium sulfate, filtered,concentrated to a small volume, diluted with isopropyl acetate andresidual water removed azeotropically. The solution is diluted withacetonitrile, warmed and adipic acid (0.13 Kg) added. The solution iscooled gradually and the solid collected, and rinsed with isopropylacetate to provide Formula 21 as a solid, 0.69 Kg, 79%, mp 119° C., HPLCpurity 95.3%. Spectral data was consistent with that of a referencestandard: ³¹P NMR (acetone-d6) 27.6; ¹³C NMR (acetone-d6) ppm 173.4,170, 162.6, 155.0, 150.4, 137.9, 137.4, 130.7, 129.3, 129.2, 129.1,127.6, 124.5, 120.4, 113.9, 108.9, 72.7, 72.6, 70.4, 70.4, 68.6, 60.7,57.8, 55.6, 54.9, 52.8, 52.3, 45.1, 42.1, 34.9, 32.6, 26.5, 26.5, 25.4,24.0, 19.2, 18.6, 13.1; ¹H NMR (acetone d-6) ppm 7.80 (d, 2H), 7.38 (t,2H), 7.29 (d, 2H), 7.28 (d, 2H), 7.26 (d, 2H), 7.21 (t, 1H), 7.12 (d,2H), 5.53 (d, 1H), 5.04 (dq, 1H), 4.95 (ddd, 1H), 4.14 (q, 2H), 3.92 (s,3H), 3.89 (m, 1H), 3.88 (dd, 1H), 3.84 (m, 1H), 3.78 (br s, 2H), 3.76(dd, 1H), 3.63 (dd, 1H), 3.60 (dd, 1H), 3.20 (dd, 1H), 3.06 (dd, 1H),2.97 (dt, 2H), 2.91 (dd, 1H), 2.85 (m, 1H), 2.70 (dd, 1H), 2.33 (m, 2H),2.24 (m, 2H), 2.04 (m, 1H), 1.67 (m, 2H), 1.51 (m, 2H), 1.51 (d, 3H),1.21 (t, 3H), 0.93 (d, 3H), 0.89 (d, 3H); IR (KBr) cm⁻¹ 3354, 3424,3300-2400 (br), 2959, 1755, 1703, 1599, 1497, 1308, 1343, 1152, 991,950.

Procedure for Formula 21b,2-[(2S,3R)-4-[((4-methoxybenzene)sulfonyl)(2-methylpropyl)amino]-3-(hydroxy)butyl]-[[[[(phenoxy)(2-(2R)-propionicacid ethyl ester)oxy]phosphinyl]ethylamino]benzyl]-[carbamicacid-(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester]butanedioate salt(1:1)

Prepared by dissolving 7.8 g of the free base Formula 29 by agitating inhot isopropyl acetate (˜200 mL), charging succinic acid (1 equivalent),and after a solution is obtained the solution is gradually cooled toambient temperature and then cooled in an ice bath for several minutes,the product collected and rinsed with isopropyl acetate and dried toconstant weight providing Formula 21b succinate salt, 7.7 g, 86%, HPLCpurity 98.6%, mp 106.5° C. ¹³C NMR (CDCl₃) 129.8, 129.4, 129.2, 124.9,120.3, 114.1, 109.0, 70.9, 72.7, 71.4, 70.33, 70.28, 69.34, 69.30, 61.3,56.51, 56.47, 55.3, 54.95, 52.24, 52.22, 51.74, 51.72, 44.93, 42.42,30.65, 24.84, 24.79, 26.48, 25.42, 19.7, 19.6, 19.24, 13.7. ¹H NMR(CDCl₃) 7.75-7.79 (d, 2H), 7.38-7.43 (d, 2H), 7.33-7.36 (m, 2H),7.24-7.29 (d, 2H), 7.15-7.20 (t, 1H), 6.98-7.05 (4H), 5.63 (d, 1H),5.00-5.08 (m, 1H), 5.84-4.92 (m, 1H), 4.09-4.18 (m, 3H), 3.93-3.98 (m,1H), 3.91 (s, 3H), 3.79-3.92 (m, 4H), 3.66-3.74 (m, 1H), 3.22-3.56 (m,4H), 2.96-3.02 (m, 2H), 2.51-2.83 (m, 10H), 1.74-1.82 (m, 2H), 1.6 (d,3H), 1.46-2.01 (3H), 1.21 (t, 3H), 1.83 (d, 3H), 1.63 (d, 3H).

Procedure for Formula 22

A flask is charged with 14.8 g of disuccidimidylcarbonate, CH₂Cl₂ (25mL), 5.0 g of Formula 10 as a solution in CH₂Cl₂ (20 mL), and pyridine(7.8 mL). The solution is heated at gentle reflux for several hoursuntil reaction completes. Heating is removed and water (35 mL) is added,the mixture agitated several minutes, the layers are separated. Theorganic phase is washed sequentially with water (35 mL) and brine (30mL). The organic phase is dried over sodium sulfate, filtered andconcentrated. The residue is redissolved in dichloromethane CH₂Cl₂ (13mL) with heating and heptane (10 mL) added to the warm solution. Themixture is gradually cooled to approximately 10° C., the solid filtered,rinsed with heptane and dried to constant weight providing ˜8.9 g 87.5%.

A flask is charged with crude Formula 22 (106 g), activated carbon (23g) and toluene (5.7 Kg). After agitation for 2 h the mixture is filteredthrough celite and the filtrate evaporated to afford 100 g (94.3%recovery) of Formula 22 as an off-white solid.

A flask is charged with Formula 22 (12 g) of Formula 22, acetone (24 g)and heated to 52° C. to obtain a solution. Heptane (60 g) is added tothe warm solution under agitation. The mixture is cooled over two hoursto approximately 10° C., the solid collected, washed the with 3:1acetone:heptane and dried to constant weight, providing Formula 22, 11.4g, 95% recovery, as a white solid. ¹H NMR (CDCl₃) 5.75 (d, 1H),5.21-5.30 (dd, 1H), 3.90-4.16 (m, 4H), 3.07-3.18 (m, 1H), 2.85 (s, 4H),2.10-2.22 (m, 1H), 1.92-2.06 (m, 1H).

Preparation of Formula 24

A flask is charged with Formula 24 (10 g), potable water (7.5 g, 13.5eq.) and isobutylamine (22.08 g, 9.8 eq.), the thick mixture heated to˜60° C., and agitated at this temperature until reaction completed. Thereaction mixture is charged with 100 mL potable water over ˜30 minuteswhile maintaining the internal temperature >55° C. The mixture is cooledto 5° C. over 1.5 hours, and held at that temperature for an additional30 minutes. The slurry is filtered, washed with 20 mL of potable water,and dried to constant weight providing Formula 23, 10.94 g; 98.4%, HPLCpurity 97.9%. ¹H NMR (CDCl₃) 7.55-7.62 (d, 2H), 7.32-7.38 (d, 2H),4.62-4.72 (broad s, 1H), 3.78-3.90 (broad m, 1H), 3.42-3.50 (m, 1H),3.08-3.16 (dd, 1H), 2.63-2.90 (m, 3H), 2.42 (d, 2H), 1.65-1.81 (m, 1H),1.35 (s, 9H), 0.93 (d, 6H).

Preparation of Formula 25

A flask is charged with Formula 23 (10.5 g), dichloromethane (63 mL) andtriethylamine (3.1 g, 1.05 eq.) and a solution of4-methoxyphenylsulfonyl chloride (6.1 g, 1.02 eq.) in dichloromethane(18 mL) added over ˜10 minutes, maintaining the internal temperature<25° C. during the addition. Following reaction completion (−2 h atambient temperature) 1M aqueous HCl (5 mL) is added, agitated for 5 min,and the layers separated. 1 M aqueous NaHCO₃ (5 mL) are added to theorganic phase and the mixture agitated for 5 min, the layers separatedand the organic phase concentrated to a foam. The crude product isdissolved in 200 mL EtOH at 65° C., water (120 mL) added over ˜45minutes, while maintaining the internal temperature >57° C., and themixture d, 2H), 7.36-7.43 (d, 2H), 6.96-7.04 (d, 2H), 4.63-4.72 (broads, 1H), 3.88 (s, 3H), 3.72-3.90 (m, 2H), 3.04-3.18 (m, 3H), 2.79-3.01(m, 3H), 1.78-1.92 (m, 1H), 1.62 (broad s, 1H), gradually cooled to 10°C. over approximately 4.5 hours. The slurry is filtered and washed with50 mL of 30% aqueous EtOH, the product dried to constant weightproviding 14.5 g, 94%, HPLC purity 99.86%. ¹H NMR (CDCl₃) 7.70-7.76 (d,2H), 7.55-7.64 (1.35 (s, 9H), 0.85-0.95 (dd, 6H).

Procedure for Formula 26

A flask is charged with Formula 25 (35 g), toluene (525 mL), inerted andcooled to −20° C. A solution of 1.5 M DIBAL-H in toluene (154 mL, 1.5 M,3.5 equiv.) is added gradually, keeping the temperature below −10° C.The reaction is agitated for several hours at this temperature untilcomplete. Methanol (9.3 mL, 3.5 eq.) is charged gradually, followed byTHF (88 mL), and the mixture warmed above 0° C. Aqueous citric acid (220ml of 40% (w/w) of citric acid, 7 eq.) diluted with 130 ml of water) isadded over 5 minutes and the mixture then warmed ˜60° C. forapproximately 1 hour. The mixture is cooled to ambient temperature, thelayers separated, and the organic layer added to 175 ml of 1M HCl and 35ml of water. The separatory funnel is rinsed forward with 105 ml of THF.The resulting mixture is agitated at room temperature for approximately1 hour, diluted with THF (35 mL), separated, the organic layer combinedwith 35 ml of 1 M NaHCO₃ and agitated for 30 minutes. The layers wereseparated, filtered through a layer of anhydrous magnesium sulfate(approximately 2 g) and rinsed with toluene (35 mL). The solution isconcentrated and azeotroped with toluene three times to decreaseresidual THF. The final volume is adjusted to approximately 275 mL andthe slurry heated ˜65° C. to attain a solution. Heptane (132 mL) isadded gradually and the mixture then gradually cooled over 4 h toambient temperature. The product is filtered, washed with 2:1toluene:heptane, and dried to constant weight, providing Formula 26, 31g, 88%, mp 120.5° C., HPLC purity 99.6%. ¹H NMR (CDCl₃) 10.0 s, 1H),7.80-7.85 (m, 4H), 7.27-7.50 (d, 2H), 7.09-7.10 (d, 2H), 5.99-6.07(broad d, 1H), 3.91 (s, 3H), 3.78-3.93 (m, 3H), 3.41-3.51 (dd, 1H),3.24-3.34 (dd, 1H), 2.79-3.05 (m, 5H), 1.29 (s, 9H), 0.87-0.93 (dd, 6H).

Procedure for formula 15,{(1S,2R)-[1-(4-Formyl-benzyl)]-(2R)-2-hydroxy-3-[N-isobutyl-(N-4-methoxy-benzenesulfonyl)-amino]-propyl}-carbamicacid [3R,3aS,6aR]-hexahydrofuro[2,3-b]furan-3-yl ester

A flask is charged with Formula 26 (2.0 g) and 20 mL THF.Methanesulfonic acid was added drop-wise to the solution. The solutionis warmed to 40° C. until de-protection was complete. The solution wascooled to 20° C. and N-methylimidazole (2.39 g) was added to thereactor. Formula 22 (1.52 g) was then charged and the reaction waswarmed to 50° C. until the reaction was complete. Ethyl acetate (150 mL)was charged and the solution was sequentially washed with 0.5 M aq.citric acid (20 g), 10% aq. NaH₂PO₄ (20 g), sat. NaHCO₃ (20 g), and 10%aq. NaH₂PO₄ (20 g). The organic layer was dried over anhydrous sodiumsulfate (2 g), filtered, and concentrated to a viscous oil which waspurified by silica gel column chromatography eluting with a mixture ofethyl acetate and heptane. The fractions containing desired Formula 15were combined and concentrated to afford a white solid, 95%, 2.13 g,HPLC purity 97%.

Reference has been made to certain embodiments of the invention,examples of which are illustrated in the accompanying description,structures and formulas. While the invention has been described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims.

What is claimed is:
 1. A process for preparing a bisfuran alcohol ofFormula 0:

comprising, reacting 2,3-dihydrofuran and a glycoaldehyde orglycoaldehyde dimer in the presence of a lanthanide or transition metalcatalyst to form the bisfuran alcohol of Formula
 0. 2. The process ofclaim 1, where the catalyst comprises Yb, Pr, Cu, Eu or Sc complexed toa ligand selected from:


3. The process of claim 2, where the catalyst is Yb(hfc)₃(+),Yb(hfc)₃(−), Eu(hfc)₃(+), Eu(hfc)₃(−), Yb(fod)₃(+) and S-Binaphthol,Yb(tfc)₃(+), Sc(OTf)₃ and (S)-pybox, and Pr(tfc)₃(+) where

where, M represents Yb, Pr, Cu, Eu or Sc.
 4. The process of claim 1,where the reaction is carried out at a temperature of between about 0°C. to about 100° C.
 5. The process of claim 1, where the reaction iscarried out in the presence of a catalyst comprising a lanthanide ortransition metal complexed to a chiral ligand.
 6. The process of claim5, where the chiral ligand is

where, Ph is phenyl.
 7. The process of claim 1, which is carried out inthe presence of a solvent.
 8. The process of claim 7, where the solventis a polar aprotic solvent.
 9. The process of claim 8, where the solventis methyl-t-butyl-ether, dichloromethane or a mixture thereof.
 10. Theprocess of claim 1, which is carried out in the presence of excess2,3-dihydrofuran as a solvent.
 11. The process of claim 1, where thecatalyst comprises Sc.
 12. The process of claim 1, where the catalystcomprises Yb.
 13. The process of claim 1, further comprising, (i)combining the bisfuran alcohol of Formula 0 with disuccinimidyldicarbonate to form a compound of Formula L1:

(ii) combining the bisfuran alcohol of Formula 0 with bis(p-nitro)phenylcarbonate or p-nitrophenol chloroformate to form a compound of FormulaL2:

or (iii) combining the bisfuran alcohol of Formula 0 with dipyridylcarbonate to form a compound of Formula L3:


14. The process of claim 13, further comprising, combining the compoundof Formula L1, L2 or L3 with a compound of Formula N,

to form a compound of Formula A,

where, Me is methyl.
 15. The process of claim 14, further comprising,combining the compound of Formula A with a compound of Formula J,

to form a compound of Formula I,

where, Me is methyl; Et is ethyl; and Ph is phenyl.
 16. The process ofclaim 15, further comprising, combining the compound of Formula I withadipic acid to form a salt of Formula IV,

where, Me, Et and Ph are each independently defined the same as in claim15.
 17. The process of claim 14, where the compound of Formula N isprepared by deprotecting a compound of Formula M:


18. The process of claim 17, where the deprotection is accomplished bycombining the compound of Formula M with a deprotecting agent which isselected from trifluoroacetic acid, hydrochloric acid, toluenesulfonicacid, methanesulfonic acid, benzenesulfonic acid, or hydrobromic acid.19. The process of claim 17, where the compound of Formula M is preparedby reducing a compound of Formula C:


20. The process of claim 19, where the reduction is accomplished bycontacting the compound of Formula C with a reducing agent which islithium aluminum hydride, sodium borohydride, lithium borohydride,sodium trisacetoxyborohydride, sodium cyanoborohydride, potassiumtriisopropoxy borohydride or diisobutyl aluminum hydride
 21. The processof claim 19, where the compound of Formula C is prepared by combining acompound of Formula F with a compound of Formula G:


22. The process of claim 21, where the compound of Formula F is preparedby combining a compound of Formula E with an amine:


23. The process of claim 22, where the amine is


24. A compound having the formula C:

or a pharmaceutically acceptable salt thereof.
 25. A compound having theformula M:

or a pharmaceutically acceptable salt thereof.
 26. A compound having theformula N:

or a pharmaceutically acceptable salt thereof.
 27. A salt having theformula IV:


28. A pharmaceutical composition comprising the salt of claim 27 and anexcipient, diluent or carrier.
 29. A method for the treatment orprophylaxis of a retrovirus infection in a patient, comprisingadministering to the patient a therapeutically effective amount of thesalt of claim
 27. 30. The method of claim 29, where the retrovirus ishuman immunodeficiency virus (HIV).
 31. The method of claim 29, wherethe therapeutically effective amount is about 10 mg to about 2000 mg.32. The method of claim 29, where the salt is administered in apharmaceutical composition.
 33. The method of claim 32, where thepharmaceutical composition is in a unit dosage form of a tablet.
 34. Themethod of claim 29, where the salt is administered orally.
 35. A kitcomprising: (1) the pharmaceutical composition of claim 28; (2)prescribing information; and (3) a container.
 36. The kit of claim 35,where the pharmaceutical composition is in a unit dosage form of atablet.
 37. A compound, composition or method as disclosed herein. 38.The use of the salt of claim 27 for the manufacture of a medicament forinhibiting activity of a retrovirus protease in a patient, comprisingadministering to the patient a therapeutically effective amount of thesalt.
 39. The use of the salt of claim 27 for the manufacture of amedicament for the treatment or prophylaxis of a retrovirus infection ina patient, comprising administering to the patient a therapeuticallyeffective amount of the salt.
 40. The use of claim 38 or 39, where theretrovirus is human immunodeficiency virus (HIV).
 41. The use of thesalt of claim 38 or 39, where the salt is administered to the patient asa single composition.
 42. The use of the salt of claim 38 or 39, wherethe salt is administered to the patient orally.
 43. The use of claim 42,where the oral administration is once a day.
 44. The use of claim 38 or39, where the patient is also receiving one or more agents selected thegroup consisting of stavudine, emtricitabine, tenofovir, emtricitabine,abacavir, lamivudine, zidovudine, didanosine, zalcitabine, phosphazide,efavirenz, nevirapine, delavirdine, tipranavir, saquinavir, indinavir,atazanavir, nelfinavir, amprenavir, samprenavir, lopinavir, ritonavir,enfuvirtide, Fozivudine tidoxil, Alovudine, Dexelvucitabine,Apricitabine, Amdoxovir, Elvucitabine (ACH126443), Racivir (racemic FTC,PSI-5004), MTV-210, KP-1461, fosalvudine tidoxil (HDP 99.0003), AVX756,Dioxolane Thymine (DOT), TMC-254072, INK-20, 4′-Ed4T, TMC-125(etravirine), Capravirine, TMC-278 (rilpivirine), GW-695634, CalanolideA, BILR 355 BS, and VRX 840773, and pharmaceutically acceptable saltsthereof.
 45. The use of claim 38 or 39, where the therapeuticallyeffective amount is about 10 mg to about 2000 mg.
 46. The use of claim38 or 39, where the salt is administered in a pharmaceuticalcomposition.
 47. The use of claim 46, where the pharmaceuticalcomposition is in a unit dosage form of a tablet.
 48. The use of claim47, where the salt is administered orally.